Abstract 1411: Different treatment response in several head and neck squamous cell carcinoma(HNSCC) cell lines reflecting underlying genomic &amp; molecular signatures
Authors: Jo-Pai Chen Chen, Jui-Ying Chang, Zhong-Zhe Lin, Ruey-Long Hong
Journal: Cancer Research (2023)

Abstract Background: The treatment of HNSCC in Taiwan is still very challenging and might be related to betel-nuts use. Betel nut chewing might contribute to (1)strong inflammation, angiogenesis, and invasion ; (2)easy recurrence; (3)refractory to traditional therapies. In our previous research, we found betel-nuts exposed HNSCC cell line, TW2.6, might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan with high PDL1, defective p53 mutation, p16 loss, and BCL2 overexpression. PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, &amp; VEGFR2/PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, &amp; PI3K/AKT/mTOR signaling and the modulation of stemness &amp; PD1/PDL1 pathway. Besides, polo like kinase inhibition seemed a good radiosensitizer for TW2.6. Methods: We try to prove the difference of TW2.6 reflecting clinical characteristics of HNSCC in Taiwan and design effective treatment combinations. Other HNSCC cell lines will also be evaluated for their genomic signatures. All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations. Results: Conclusions: Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC. Specific Tx for TW2.6 &amp; others are listed above. Cell lines SCC25 KB SAS CAL27 FaDu SCC15 SCC9 SCC4 TW2.6 Differ- entiation Well Poor Poor Poor Poor Well Well Well Well, but rapidly replicated, with high hyper-diploidy &amp; complex rearrangements HPV status HPV 16/18 HPV18 - - HPV 16/18 - - HPV 6/11 - EGFR status Medium Low High High Medium High Low Medium to high Unknown Docetaxel sensitivity +++ +++ ++ ++ + ++ to +++ ++ - + Cisplatin sensitivity +++ ++ +++ ++ ++ + - to + - - to + 5-FU sensitivity +++ + ++ +++ ++ - + to ++ - - to + Afatinib sensitivity +++ - to + - + ++ ++ to +++ +++ +++ - Polo-like kinase Inhibitor sensitivity +++ +++ ++ ++ + ++ to +++ - to + - - to + VEGFR2 Inhibitor sensitivity - - - - ++ +++ - - ++ PI3K/mTOR inhibitor All cell lines sensitive CDK4/6 Inhibitor response +++ - to + +++ ++ to +++ + ++++ + ++ ++ to +++ Western blots Weak p-AKT &amp; VEGF-A, mild PDL1 and BMI-1, Gli-1(+) Weak p-AKT, mild PDL1 and strong VEGF-A &amp; BMI-1, p16(+) Moderate p-AKT &amp; BMI-1, high PDL1, mild VEGF-A High p-AKT &amp; VEGF-A, mild PDL1 &amp; BMI-1 High VEGF-A, moderate p-AKT &amp; PDL1, weak BMI-1, Gli-1(+) Weak p-AKT &amp; VEGF-A, mild PDL1 &amp; BMI-1 Weak p-AKT, VEGF-A, &amp; BMI-1, moderate PDL1 Moderate p-AKT &amp; VEGF-A, strong BMI-1, mild PDL1, Gli-1(+) High p-AKT, PDL1, &amp; VEGF-A and moderate BMI-1 NGS CCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutation STK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutation KRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutation CDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutation CCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutation CCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutation CDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutation CCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutation FAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B loss Outcomes Best; like TCGA CL (HPV+) subtype Like TCGA basal subtype, but responded to particular treatments each Basal Basal Like TCGA mesen-chymal subtype (HPV+) Like TCGA CL(HPV-) subtype, different characters between these 3 cell lines CL(HPV-) subtype CL(HPV-) subtype Worse; like TCGA EMT subtype (HPV-) Potential treatments All sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried (1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O (1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor (1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics (1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi &amp; CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi (1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,&amp; p53 reactivator (1) Taxane &amp;5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi (1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator (1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Citation Format: Jo-Pai Chen Chen, Jui-Ying Chang, Zhong-Zhe Lin, Ruey-Long Hong. Different treatment response in several head and neck squamous cell carcinoma(HNSCC) cell lines reflecting underlying genomic &amp; molecular signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1411.